Tumour-associated antigens (TAAs), recognized by the immune system of a cancer patient, may represent important immunotherapeutic targets. Evidence in support of this has been provided by autologous bone marrow transplantation and donor lymphocyte infusion studies, demonstrating that donor cells can recognize and respond to TAAs in a variety of haematological malignancies such as multiple myeloma and myeloid leukaemia (Bellucci et al 2004, Porter et al 2006, Atanackovic et al 2007). Furthermore, vaccination studies have reported an increased immune response to TAAs (Rezvani et al 2007, Schmitt et al 2008). It is also of note that the immune response signature has been identified as being of importance in predicting survival in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (Dave et al 2004, Monti et al 2005).
TAAs that are of current interest for improving treatment regimens are the cancer testis antigens (CTAs). Their restricted normal tissue distribution but widespread expression in tumours makes them attractive immunotherapeutic targets, while minimizing potential problems with autoimmunity (Scanlan et al 2004, Simpson et al 2005, Suri 2006). Initially, studies of CTA expression focussed on solid tumours (Simpson et al 2005), but there are increasing reports of CTAs being expressed in haematological malignancies such as multiple myeloma (Pellat-Deceunynck et al 2000, Chiriva-Internati et al 2001, Lim et al 2001, Sugita et al 2004, van Rhee et al 2005, Goodyear et al 2005, Jungbluth et al 2005) and myeloid malignancies (Adams et al 2002, Zhang et al 2003, Andrade et al 2008, Tinguely et al 2008). Indeed, a gene expression profiling study reported transcripts of multiple CTAs in myeloma tumour cells (Condomines et al 2007). Other studies have also reported the presence of cytotoxic T cells (CTLs), considered to be the major effector cells in cellular immunity, to CTAs such as NY-ESO-1 and Sp17 in the peripheral blood of multiple myeloma patients, thereby suggesting the presence of spontaneous immunity to these CTAs (van Rhee et al 2005, Goodyear et al 2005). There is also accumulating evidence for a major role for CD4+ T-helper (TH) cells not only in the regulation and maintenance of the CTL and humoural responses but also in the ability of the TH themselves to control tumour cell growth (Oestrand-Rosenberg et al 2005), Goodyear et al 2008). A subsequent investigation has shown that this immunity can be boosted through vaccination with antigens such as NY-ESO-1 (Baumgaertner et al 2006, Odunzi et al 2007) and clinical trials are ongoing using CTAs as vaccine targets (Szmania et al 2006, Odunzi et al 2007).
The present inventors previously used the SEREX technique, which exploits the circulating antibodies present in the serum of patients, to identify the PAS (Per ARNT Sim) domain containing 1 (PASD1) protein or CT63, encoded by a gene at Xq28, as a lymphoma-associated antigen and candidate CTA (Liggins et al 2004a, Liggins et al 2004b). Two splice variants were identified, PASD1a (639 amino acids) and PASD1b (773 amino acids). The first 638 amino acids are common to both proteins (Liggins et al 2004a). This work is described by International Patent Application Publication No. WO 03/082916, which is incorporated by reference in its entirety.
The production of monoclonal antibodies to PASD1 allowed confirmation of this molecule as a novel CTA with a highly restricted expression pattern in normal tissues and more specifically as a CT-X antigen expressed in a range of haematological malignancies (Cooper et al 2006, Sahota et al 2006).